Magrolimab plus azacitidine: good ORR in MDS/AML

Anti-CD47 magrolimab in combination with azacitidine is well-tolerated, and demonstrates robust activity in myeloid dysplastic syndrome (MDS) and acute myeloid leukaemia (AML), including seemingly durable responses. Initial data indicate particular benefit for patients with TP53 mutations.

Prof. Naval Draver (University of Texas MD Anderson Cancer Centre, USA) presented the results of a phase 1b trial [1] examining the anti-CD47 antibody magrolimab in combination with azacitidine in patients with AML or high-risk MDS. The rationale of this study, he explained, is that CD47 is an immune checkpoint that lies on the surface of macrophages in AML. AML blast cells link CD47 to signal regulatory protein α. Because CD47 is a "do not eat me" signal, overexpression in AML leads to macrophage suppression and exhaustion, with consequent tumour evasion of phagocytosis by macrophages. Blocking CD47 with the first-in-class magrolimab, the investigators hypothesised, should lead to engulfment of leukaemic cells and reduction of tumour load. Moreover, preclinical data in immunodeficient mouse models have demonstrated prolonged survival and rapid responses with magrolimab in combination with the hypomethylating agent azacitidine [2]. Besides safety, co-primary endpoints were the objective response rate (ORR; response assessments according to 2006 IWG MDS criteria) and 8-week RBC transfusion-independence rate.

In total, 68 patients with either AML or high-risk MDS were treated with magrolimab in combination with azacitidine. The safety profile of the combination of magrolimab plus azacitidine was consistent with known effects of each agent individually, and no maximum tolerated dose was reached. Common all-grade treatment-related adverse events were anaemia (38%), fatigue (21%), neutropenia (19%), thrombocytopenia (18%), and infusion site reaction (16%). Only 1 patient discontinued the trial due to treatment-related adverse events.

The ORR primary endpoint was also met; of the 33 previously untreated high-risk MDS patients who were evaluable for efficacy, 91% achieved an objective response, including 42% with a complete remission (CR). Responses to magrolimab and azacitidine deepened over time, as the CR rate with >6 months of follow-up rose to 56%. In patients with previously untreated AML (n=25), 64% achieved an objective response, including 56% with a CR or a CR with incomplete blood count recovery (CRi). Notably, of the patients whose AML was characterised by a TP53-mutation (n=12), a particularly treatment-refractory and poor prognosis population, 75% achieved a CR or CRi. In total, 58% of RBC transfusion-dependent patients became transfusion-independent for at least 8 weeks. Median duration of response and median overall survival have not yet been reached. Follow-up and expansion cohorts are ongoing.

In short, magrolimab in combination with azacitidine is well-tolerated, and demonstrates robust activity in MDS and AML, including seemingly durable responses. Initial data indicate that this combination may be particularly effective but not exclusive against blast cells carrying TP53 mutation, a treatment-refractory subgroup. Registrational studies are being initiated.

1. 
   
   1. Draver N, et al. The first-in-class anti-CD47 antibody magrolimab combined with azacitidine is well-tolerated and effective in AML patients: phase 1b results. EHA25 Virtual, 11-21 June 2020, Abstract S144.
   2. Chao MP, et al. Therapeutic Targeting of the Macrophage Immune Checkpoint CD47 in Myeloid Malignancies. Front Oncol. 2020;9:1380.

Posted on 9 September, 202029 February, 2024